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Inhibition of IκB Kinase Is a Potential Therapeutic Strategy to Circumvent Resistance to Epidermal Growth Factor

Yong Weon Yi1, Kyu Sic You1,2, Sanghee Han3

  • 1Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea.

Cancers
|November 11, 2022
PubMed

Insights

Combining gefitinib (EGFR inhibitor) with IKK16 (IKK inhibitor) shows synergistic effects against triple-negative breast cancer (TNBC). This combination targets the IKK/NF-κB pathway, offering a new therapeutic strategy for this intractable malignancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) presents limited therapeutic options and poor prognosis, despite high epidermal growth factor receptor (EGFR) expression.
  • Previous EGFR-targeted therapies have shown unfavorable clinical outcomes in TNBC.

Purpose of the Study:

  • To identify novel therapeutic strategies for TNBC by screening protein kinase inhibitors in combination with gefitinib.
  • To investigate the synergistic effects and underlying mechanisms of gefitinib combined with IKK inhibitor IKK16 in TNBC.

Main Methods:

  • Combinatorial screening of 55 protein kinase inhibitors with gefitinib in MDA-MB-231 TNBC cells.
  • Cell viability, clonogenic survival, Western blot, and next-generation sequencing (NGS) analyses were performed.
  • Evaluated the antiproliferative effects and molecular mechanisms of the Gefitinib + IKK16 combination in TNBC cell lines.

Main Results:

  • Gefitinib + IKK16 synergistically reduced cell viability and colony formation in TNBC cell lines (HS578T, MDA-MB-231, MDA-MB-468).
  • The combination downregulated key signaling pathways including p-STAT3, p-AKT, p-mTOR, p-GSK3β, p-RPS6, and regulated p-NF-κB and total NF-κB.
  • NGS revealed reduced expression of NF-κB/RELA targets (e.g., CCL2, IL-6) and synergistic induction of tumor suppressors (e.g., FABP3, SEMA6A).

Conclusions:

  • The IKK/NF-κB pathway is a viable target for combination therapy with EGFR inhibition in TNBC.
  • Gefitinib + IKK16 demonstrates significant preclinical efficacy, suggesting a promising therapeutic approach for TNBC.
Keywords:
IκB kinase (IKK) inhibitionanticancercombinationepidermal growth factor receptor (EGFR) inhibitiongefitinibkinase inhibitorresistancesynergismtriple-negative breast cancer (TNBC)

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